Randomized controlled phase 2 trial of hydroxychloroquine in childhood interstitial lung disease

Background No results of controlled trials are available for any of the few treatments offered to children with interstitial lung diseases (chILD). We evaluated hydroxychloroquine (HCQ) in a phase 2, prospective, multicentre, 1:1-randomized, double-blind, placebo-controlled, parallel-group/crossover trial. HCQ (START arm) or placebo were given for 4 weeks. Then all subjects received HCQ for another 4 weeks. In the STOP arm subjects already taking HCQ were randomized to 12 weeks of HCQ or placebo (= withdrawal of HCQ). Then all subjects stopped treatment and were observed for another 12 weeks. Results 26 subjects were included in the START arm, 9 in the STOP arm, of these four subjects participated in both arms. The primary endpoint, presence or absence of a response to treatment, assessed as oxygenation (calculated from a change in transcutaneous O 2 -saturation of ≥ 5%, respiratory rate ≥ 20% or level of respiratory support), did not differ between placebo and HCQ groups. Secondary endpoints including change of O 2 -saturation ≥ 3%, health related quality of life, pulmonary function and 6-min-walk-test distance, were not different between groups. Finally combining all placebo and all HCQ treatment periods did not identify significant treatment effects. Overall effect sizes were small. HCQ was well tolerated, adverse events were not different between placebo and HCQ. Conclusions Acknowledging important shortcomings of the study, including a small study population, the treatment duration, lack of outcomes like lung function testing below age of 6 years, the small effect size of HCQ treatment observed requires careful reassessments of prescriptions in everyday practice (EudraCT-Nr.: 2013-003714-40, www.clinicaltrialsregister.eu , registered 02.07.2013)

Genes related to mitochondrial functions are differentially expressed in phosphine-resistant and -susceptible Tribolium castaneum

Background: Phosphine is a valuable fumigant to control pest populations in stored grains and grain products. However, recent studies indicate a substantial increase in phosphine resistance in stored product pests worldwide.Results: To understand the molecular bases of phosphine resistance in insects, we used RNA-Seq to compare gene expression in phosphine-resistant and susceptible laboratory populations of the red flour beetle, Tribolium castaneum. Each population was evaluated as either phosphine-exposed or no phosphine (untreated controls) in triplicate biological replicates (12 samples total). Pairwise analysis indicated there were eight genes differentially expressed between susceptible and resistant insects not exposed to phosphine (i.e., basal expression) or those exposed to phopshine (>8-fold expression and 90 % C.I.). However, 214 genes were differentially expressed among all four treatment groups at a statistically significant level (ANOVA, p < 0.05). Increased expression of 44 cytochrome P450 genes was found in resistant vs. susceptible insects, and phosphine exposure resulted in additional increases of 21 of these genes, five of which were significant among all treatment groups (p < 0.05). Expression of two genes encoding anti-diruetic peptide was 2- to 8-fold reduced in phosphine-resistant insects, and when exposed to phosphine, expression was further reduced 36- to 500-fold compared to susceptible. Phosphine-resistant insects also displayed differential expression of cuticle, carbohydrate, protease, transporter, and many mitochondrial genes, among others. Gene ontology terms associated with mitochondrial functions (oxidation biological processes, monooxygenase and catalytic molecular functions, and iron, heme, and tetrapyyrole binding) were enriched in the significantly differentially expressed dataset. Sequence polymorphism was found in transcripts encoding a known phosphine resistance gene, dihydrolipoamide dehydrogenase, in both susceptible and resistant insects. Phosphine-resistant adults also were resistant to knockdown by the pyrethroid deltamethrin, likely due to the increased cytochrome P450 expression.Conclusions: Overall, genes associated with the mitochondria were differentially expressed in resistant insects, and these differences may contribute to a reduction in overall metabolism and energy production and/or compensation in resistant insects. These data provide the first gene expression data on the response of phosphine-resistant and -susceptible insects to phosphine exposure, and demonstrate that RNA-Seq is a valuable tool to examine differences in insects that respond differentially to environmental stimuli.Peer reviewedEntomology and Plant Patholog

Ligand sensitivity of the α2 subunit from the bovine cone cGMP-gated channel is modulated by protein kinase C but not by calmodulin

Homomeric cyclic nucleotide-gated (CNG) channels composed of α2 subunits from bovine cone photoreceptors were heterologously expressed in the human embryonic kidney (HEK) 293 cell line. Modulation of cGMP sensitivity by protein kinase C (PKC)-mediated phosphorylation and by binding of calmodulin (CaM) was investigated in inside-out patches.A peptide encompassing the putative CaM-binding site within the N-terminus of the channel protein binds Ca2+-CaM with high affinity, yet the ligand sensitivity of α2 channels is not modulated by CaM.PKC-mediated phosphorylation increased the activation constant (K1/2) for cGMP from 19 to 56 μm and decreased the Hill coefficient (from 2.5 to 1.5). The change in ligand sensitivity involves phosphorylation of the serine residues S577 and S579 in the cGMP-binding domain. The increase in K1/2 was completely abolished in mutant channels in which the two serine residues were replaced by alanine.An antibody specific for the δ isoform of PKC strongly labels the cone outer segments.Modulation of cGMP affinity of bovine α2 CNG channels by phosphorylation could play a role in the regulation of photoreceptor sensitivity

Selective ribosome profiling reveals a role for SecB in the co-translational inner membrane protein biogenesis

The chaperone SecB has been implicated in de novo protein folding and translocation across the membrane, but it remains unclear which nascent polypeptides SecB binds, when during translation SecB acts, how SecB function is coordinated with other chaperones and targeting factors, and how polypeptide engagement contributes to protein biogenesis. Using selective ribosome profiling, we show that SecB binds many nascent cytoplasmic and translocated proteins generally late during translation and controlled by the chaperone trigger factor. Revealing an uncharted role in co-translational translocation, inner membrane proteins (IMPs) are the most prominent nascent SecB interactors. Unlike other substrates, IMPs are bound early during translation, following the membrane targeting by the signal recognition particle. SecB remains bound until translation is terminated, and contributes to membrane insertion. Our study establishes a role of SecB in the co-translational maturation of proteins from all cellular compartments and functionally implicates cytosolic chaperones in membrane protein biogenesis

Eine Frage der Perspektive

Mit dem Buchtitel „Eine Frage der Perspektive“ werden mehrere hochaktuelle Themen gleichzeitig angesprochen: Zum einen verhandelt der Band den Erkenntnisgewinn aus einem Objekt durch dessen reine Betrachtung, zum anderen hilft gerade der Perspektivwechsel auf ein Objekt dabei, wissenschaftliche Arbeitshypothesen und Theorien zu formulieren. Der Band illustriert, wie die Sichtweisen von heute berücksichtigt werden, wenn alte Objekte und deren Sammlungskontexte unter neuen ethischen und moralischen Wertevorstellungen untersucht werden. So gesellen sich zu den klassischen Objektthemen in diesem Band auch der Blick der Provenienzforschung, die künstlerische Objektauseinandersetzung, die autoethnographische Objektbeschreibung und die Frage, wie weit der Begriff eines musealen Objekts überhaupt gefasst werden kann und wie entsprechend eine Kategorisierung und Benennung erfolgen sollte. Besonders die hier enthaltenen Objektgeschichten schlagen den großen Bogen von den Forschungsinhalten zu deren Vermittlung. Dieser Band vereint elf Beiträge von Nachwuchswissenschaftlerinnen und Nachwuchswissenschaftlern aus den Bereichen Museologie, Archivkunde, Ethnologie, Physik-, Medizin- und Theatergeschichte, Humananatomie, Mathematikdidaktik, Geologie, Paläontologie und aus der Freien Kunst. Sie alle haben die Betrachtung von Sammlungsobjekten aus verschiedenen Perspektiven zum Inhalt. Die Beiträge zeigen deutlich, dass Objekte Wissenschaft hervorragend transportieren können, oft anschaulicher, als es Texte oder Bilder vermögen. Objektbasierter Wissenstransfer fördert eine gegenständliche und damit oft einfacher verständliche Wissenschaft. Diese Klammer vom Objekt über die Forschung zur Reflexion über Forschung ist die Stärke dieses fünften Bandes zum Jungen Forum für Sammlungs- und Objektforschung.Peer Reviewe